Second generation antipsychotics (SGAs) are commonly administered to children and adolescents for major psychiatric disorders, attention deficit disorder, and irritability associated with autism. Side effects from these medications include hyperprolactinemia, hypogonadism, and obesity. Recent studies have linked SGAs to reduced bone mineral density and increased fracture risk in humans, but it is unclear whether SGA administration in youth will have lasting deleterious effects on skeletal homeostasis. Understanding the mechanism of bone complications from SGA use is important for planning of prevention and treatment strategies in the clinic. Unlike first generation antipsychotics (FGAs), SGAs bind multiple receptors including dopamine, serotonin, histamine and alpha-adrenergic receptors and could therefore affect multiple tissues and organ systems. Recent evidence from rodents and humans suggest a major role for serotonin in regulation of bone remodeling, and bone cells express receptors (including serotonin receptors) that could be affected by SGAs. I have preliminary data demonstrating metabolic changes, including adipose redistribution to liver and bone marrow, accompanied by reduced trabecular bone mineral density in mice treated with risperidone, one of the most commonly prescribed SGAs. Bone changes are likely due to increased bone resorption, with little change in trabecular bone formation. However, periosteal circumference is also reduced after risperidone treatment, suggesting impaired periosteal osteoblast function. I have also found increased osteoclast size and number in primary bone marrow cultures treated with risperidone. I hypothesize that risperidone treatment alters whole-body metabolism and homeostasis in a manner that results in impaired bone health as well as acts directly on osteoblasts and osteoclasts to disrupt normal skeletal modeling and remodeling. I therefore propose two aims: (1) Examine the skeletal effects of 4-week risperidone administration in 8, 12 and 16 week old female mice and draw associations between bone changes and metabolic abnormalities, estrus cycling, and prolactin levels;I will also treat 4-week old mice for 4 weeks and observe changes in bone remodeling, metabolism and endocrine profiles until 20 weeks of age to determine if risperidone treatment in adolescents could permanently damage skeletal and metabolic homeostasis;(2) Test whether risperidone could have direct effects on osteoclast differentiation and function, osteoblast-dependent osteoclast recruitment, and/or osteoblast differentiation and function using in vitro primary bone cell culture and co-culture techniques. The results from these studies will establish the bone consequences of risperidone use, test whether indirect and/or direct effects of risperidone on bone cause these changes, and provide a stepping stone for future research on bone and metabolic effects of other SGAs. My results will also add to the increasing evidence for a key role of the nervous system in regulating skeletal homeostasis. PUBLIC HEALTH RELEVANCE: Second generation antipsychotics are indicated for use in adults, adolescents and children as young as five years old for major psychiatric disorders and irritability associated with autism. Risperidone is one such drug that causes hyperprolactinemia and obesity, and has recently been linked to reduced bone mineral density in patients. The proposed work will test whether uncoupled skeletal remodeling from risperidone is the result of metabolic and hormone-associated side effects and/or direct effects of risperidone on bone cells using C57BL/6 mice.